Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons.

Nuclear dysfunction in motor neurons has been hypothesized to be a principal cause of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we investigated the mechanism by which the nuclear pore complex (NPC) is disrupted in dying motor neurons in a mechanistic ALS mouse model (adenosine deaminase acting on RNA 2 (ADAR2) conditional knockout (AR2) mice) and in ALS patients. We showed that nucleoporins (Nups) that constituted the NPC were cleaved by activated calpain via a Ca2+-permeable AMPA receptor-mediated mechanism in dying motor neurons lacking ADAR2 expression in AR2 mice. In these neurons, nucleo-cytoplasmic transport was disrupted, and the level of the transcript elongation enzyme RNA polymerase II phosphorylated at Ser2 was significantly decreased. Analogous changes were observed in motor neurons lacking ADAR2 immunoreactivity in sporadic ALS patients. Therefore, calpain-dependent NPC disruption may participate in ALS pathogenesis, and inhibiting Ca2+-mediated cell death signals may be a therapeutic strategy for ALS.

运动神经元的核功能障碍被假定为肌萎缩侧索硬化症（ALS）发病机制的主要原因。在此，我们研究了在一种机制性ALS小鼠模型（作用于RNA 2的腺苷脱氨酶（ADAR2）条件性敲除（AR2）小鼠）以及ALS患者中，核孔复合体（NPC）在濒死运动神经元中是如何被破坏的机制。我们发现，在AR2小鼠中缺乏ADAR2表达的濒死运动神经元里，构成NPC的核孔蛋白（Nups）被激活的钙蛋白酶通过一种钙离子可渗透的AMPA受体介导的机制切割。在这些神经元中，核质运输被破坏，在丝氨酸2位点磷酸化的转录延伸酶RNA聚合酶II的水平显著降低。在散发性ALS患者中缺乏ADAR2免疫反应性的运动神经元中也观察到了类似的变化。因此，钙蛋白酶依赖性的NPC破坏可能参与了ALS的发病机制，抑制钙离子介导的细胞死亡信号可能是ALS的一种治疗策略。